CN115626922A - 5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidin-4-ol derivatives and uses thereof - Google Patents

5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidin-4-ol derivatives and uses thereof Download PDF

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CN115626922A
CN115626922A CN202210423392.7A CN202210423392A CN115626922A CN 115626922 A CN115626922 A CN 115626922A CN 202210423392 A CN202210423392 A CN 202210423392A CN 115626922 A CN115626922 A CN 115626922A
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alkyl
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tetrahydropyrido
halogen
hydrogen
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陈科
蒋钰
季明华
罗欢
马海燕
韩菲
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Nhwa Pharmaceutical Corp
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Abstract

The invention relates to the field of chemical medicine, in particular to 5,6,7,8-tetrahydropyrido [4,3-d]The pyrimidine-4-ol derivative has a specific structure shown in formula I, has good sigma 1 receptor affinity and selectivity, is a strong selective agonist of sigma 1 receptor,

Description

5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidin-4-ol derivatives and uses thereof
the present application claims priority of prior application of patent application No. CN202110473156.1, entitled "5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidin-4-ol derivative and its application", filed from 29/04 to 29/2021 to the intellectual property office of China. The entire contents of said prior application are incorporated by reference into the present application.
Technical Field
The invention relates to the field of medicinal chemistry, in particular to 5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine-4-alcohol derivatives and application thereof, and also relates to a preparation method and a pharmaceutical composition of the compounds.
Background
Psychiatric, depression is defined as an affective disorder. Depression is a chronic, highly recurrent and highly disabling psychiatric disease, the first disease that causes people to lose work and life. The traditional antidepressant has delayed action and slow onset of action, and generally takes more than 2-3 weeks to take effect; in addition, the response rate of the traditional antidepressant drug is not high, wherein 30 percent of patients with depression do not respond, and 30 percent of patients only partially respond; in addition, the traditional antidepressant drugs are easy to generate drug resistance, and once the drug resistance is generated, the treatment effect is greatly reduced.
Cognitive impairment caused by depression is an unmet clinical need, has a high incidence rate, and seriously affects people's work and life. At present, the available treatment medicines are limited, mainly the acetylcholine enzyme medicine donepezil, but the medicines have obvious side effects of causing twitching, rigor and the like.
Anxiety disorder is also called anxiety disorder, and is a mental disorder with anxiety symptoms as main clinical phases, including panic disorder, generalized anxiety disorder and social anxiety disorder. The clinical symptoms are usually manifested as nervous, anxious and anxious mental symptoms accompanied by physical symptoms of autonomic hyperfunction. The anxiety disorder has high comorbidity rate, can be used for simultaneously treating one or more mental disorders, and the treatment medicines comprise common antidepressants, benzodiazepines and 5-HT1A agonists represented by buspirone. The benzodiazepines have large side effects, other medicines have small improvement degree on anxiety, and the curative effect needs to be improved.
Sigma-1 receptor (Sigma 1 receptor) is an emerging drug target in recent years and is a binding protein for various specific psychotropic drugs. The Sigma-1 receptor is a ligand-regulated chaperone that exerts its chaperone effect by interacting with receptors such as NMDA: regulate NMDA, APMA plasma channels and downstream receptors, thereby regulating mitochondrial function and releasing 5-hydroxytryptamine, dopamine and other neurotransmitters.
Known sigma-1 receptor agonists such as opipramol, igomerine, SA-4503, ANAVEX2-73, etc. have clinically shown antidepressant, anxiolytic effects. Such as benzomorphanes (SKF 10047, dextromethorphan), SSRI antidepressants (fluvoxamine, sertraline, fluoxetine, etc.), and the like, all have high affinity for the Sigma-1 binding site.
Currently, the prior art discloses different Sigma-1 receptor agonists, such as: ligand molecules with obvious antidepressant action, such as Igmesine, cutamesine, OPC-14523, opipramol, PRE-084, SA-4503, ANAVEX2-73, ANAVEX1-41, ANAVEX3-71d and the like; patent WO2017190109 discloses the structure of partial sigma receptor agonists and the use for CNS related diseases.
However, the most advanced clinical Igmesine has been declared to fail in the clinical phase 3 experiment, and Opipramol which is marketed is directed to sigma-1 targets and also is a dopamine D2 antagonist and a histamine H1 antagonist, and the multi-target effect brings certain side effects.
Considering the potential application of Sigma-1 receptor agonist in the field of neuropsychiatric diseases such as depression and anxiety, no single effective Sigma-1 receptor agonist is yet on the market as an antidepressant. Therefore, finding compounds with potent and selective pharmacological activity towards the Sigma-1 receptor and with good "pharmaceutically acceptable" properties is of great importance for clinical applications.
Disclosure of Invention
The invention aims to solve at least one technical problem in the prior art, and therefore an object of the invention is to provide a series of 5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine-4-alcohol compounds with unique structures, which have high affinity and selectivity for sigma-1 receptors, are strong selective agonists for S1R receptors, and can be used for treating mental and neurological diseases such as depression, anxiety, neurodegeneration and the like.
In a first aspect, the present invention provides a compound of formula IA or a pharmaceutically acceptable salt thereof:
Figure BDA0003607425300000021
wherein W is CH or N;
R 1a selected from substituted or unsubstituted straight or branched alkyl, cycloalkyl, said substituents being selected from halogen, C 1-5 Alkyl of (C) 3-7 Cycloalkyl of (a);
R 2a selected from hydrogen, halogen, alkyl, halogenated alkyl or alkoxy;
R 3a selected from hydrogen or alkyl;
R 4a is selected from six-membered aromatic ring, six-membered aromatic heterocycle and five-membered aromatic heterocycle, wherein the six-membered aromatic ring, six-membered aromatic heterocycle and five-membered aromatic heterocycle are optionally substituted by one or more substituents which are independently selected from hydrogen, halogen, alkyl, haloalkyl or alkoxy;
preferably R 4a Is phenyl, pyridine, pyridazine, furan, pyrrole, pyrazole or isoxazole optionally substituted by one or more substituents independently selected from halogen, C 1-5 Alkyl of (C) 1-5 Haloalkyl or C 1-5 An alkoxy group of (2).
In a preferred embodiment, in the compound of formula IA, W is N, and R is 4a Selected from the groups Ia, ib, ic, id or Ie;
or, W is CH, and R 4a Selected from the group consisting of: group Ib or Ic:
Figure BDA0003607425300000031
wherein
Figure BDA0003607425300000032
Representing the position of the connecting key;
R 5a is independently selected from C 1-5 Alkyl radical, C 1-5 Haloalkyl or C 1-5 Alkoxy of (2);
R 6a independently selected from C 1-5 An alkyl group.
In a preferred embodiment, a compound of formula IA as described above, or a pharmaceutically acceptable salt thereof, wherein R is 1a Independently selected from C 1-8 Alkyl radical, C 3-7 Cycloalkyl-substituted C 1-8 Alkyl radical, C 1-5 Haloalkyl or C 3-7 A cycloalkyl group;
said R is 2a Independently selected from hydrogen, halogen, C 1-5 Alkyl radical, C 1-5 Haloalkyl or C 1-5 An alkoxy group;
the R is 3a Independently selected from hydrogen or C 1-5 An alkyl group.
Further preferably, said R 1a Is independently selected from C 3-7 Cycloalkyl-substituted C 1-8 Alkyl, more preferably, said R 1a Independently selected from cyclopropylmethyl or cyclobutylmethyl.
Preferably, said R is 2a 、R 3a Independently selected from hydrogen or C 1-5 Alkyl, more preferably, said R 2a 、R 3a Independently selected from hydrogen, methyl, ethyl or isopropyl.
Preferably, said R 5a Independently selected from methylTrifluoromethyl or methoxy;
preferably, said R is 6a Independently selected from methyl, ethyl or isopropyl, more preferably methyl.
In another aspect, the invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:
Figure BDA0003607425300000033
wherein R is 1 Selected from substituted or unsubstituted straight or branched alkyl, cycloalkyl, said substituents being selected from halogen, C 1-5 Alkyl of (C) 3-7 Cycloalkyl groups of (a);
R 2 selected from the group consisting of hydrogen, halogen, substituted or unsubstituted straight or branched alkyl, alkoxy, said substituents being selected from the group consisting of halogen;
R 3 any one selected from hydrogen, straight chain or branched chain alkyl;
R 4 the aromatic heterocyclic compound is selected from six-membered aromatic ring, six-membered aromatic heterocyclic ring and five-membered heterocyclic ring, wherein the six-membered aromatic ring, the six-membered aromatic heterocyclic ring and the five-membered heterocyclic ring are optionally substituted by one or more substituents, and the substituents are independently selected from any one of hydrogen, halogen, alkyl, halogenated alkyl and alkoxy.
In a preferred embodiment, the compound of formula I, or a pharmaceutically acceptable salt thereof:
Figure BDA0003607425300000041
wherein
R 1 Selected from substituted or unsubstituted straight or branched C 1-8 Alkyl of (C) 3-7 Said substituents being selected from halogen, C 1-5 Alkyl of (C) 3-7 Cycloalkyl groups of (a);
R 2 selected from hydrogen, halogen, straight or branched C 1-5 Alkyl of (C) 1-5 Haloalkyl or C 1-5 The substituents are selected from halogen;
R 3 selected from hydrogen, straight or branched C 1-5 Any one of the alkyl groups of (a);
R 4 selected from phenyl, pyridine, pyridazine, furan, pyrrole, pyrazole or isoxazole, optionally substituted with one or more substituents independently selected from hydrogen, halogen, C 1-5 Alkyl of (C) 1-5 Halogenated alkyl group of (C) 1-5 Any one of the alkoxy groups of (1).
In a preferred embodiment, the compound of formula I is a compound of formula I-1:
Figure BDA0003607425300000042
wherein R is 1 ' is selected from substituted or unsubstituted straight or branched C 1-8 Alkyl of (C) 3-7 Said substituents being selected from halogen, C 1-5 Alkyl of (C) 3-7 Cycloalkyl groups of (a);
R 2 ' is selected from hydrogen, halogen, C 1-5 Alkyl of (C) 1-5 Haloalkyl or C 1-5 Alkoxy group of (a);
R 3 ' is selected from hydrogen, straight or branched C 1-5 Any one of the alkyl groups of (a);
R 5 ' is selected from halogen, C 1-8 Alkyl, C substituted by one or more halogens 1-8 Alkyl or C 1-5 Alkoxy group of (a);
A 1 、A 2 independently selected from N, C or CH.
In a preferred embodiment, the compound of formula I is a compound of formula I-2:
Figure BDA0003607425300000051
wherein R is 1 ' is selected from substituted or unsubstituted straight or branched C 1-8 Alkyl of (C) 3-7 Said substituents being selected from halogen, C 1-5 Alkyl of (C) 3-7 Cycloalkyl groups of (a);
R 2 ' is selected from hydrogen, halogen, C 1-5 Alkyl of (C) 1-5 Haloalkyl or C 1-5 Alkoxy of (2);
R 3 ' is selected from hydrogen, straight or branched C 1-5 Any one of the alkyl groups of (a);
R 6 ' absent or selected from C 1-8 Alkyl or C substituted by one or more halogens 1-8 Alkyl group of (1).
R 7 ' is selected from hydrogen, straight or branched C 1-5 Any one of the alkyl groups of (a);
R 8 ' is selected from hydrogen, straight or branched C 1-5 Any one of the alkyl groups of (a);
A 3 any one selected from N, C, CH or O;
A 4 any one selected from N, CH; and A is 3 、A 4 Not simultaneously C.
Further preferred are compounds of formula I-1 or formula I-2 wherein R is 1 ' is independently selected from straight or branched chain C 1-5 Alkyl or
Figure BDA0003607425300000052
Wherein n1 and n2 are independently selected from integers of 1-5; more preferably, said R 1 ' is independently selected from
Figure BDA0003607425300000053
Wherein n1 is 1 and n2 is 1 or 2.
Further preferred are compounds of formula I-1 or formula I-2 wherein R is 2 ' is independently selected from hydrogen or C 1-5 Alkyl, more preferably hydrogen, methyl or ethyl;
further preferred are compounds of formula I-1 or formula I-2 wherein R is 3 ' is independently selected from hydrogen, straight or branched chain C 1-5 Any one of alkyl groups of (a); more preferably hydrogen, methyl, ethyl or isopropyl;
further preferred are compounds of formula I-1 or formula I-2 wherein R is 5 ' is independently selected from methyl, trifluoromethyl or methoxy.
Still further, the compound of formula IA or formula I, or a pharmaceutically acceptable salt thereof, is selected from any one of the following compounds:
6- (cyclobutylmethyl) -4- (1- (6- (trifluoromethyl) pyridin-3-yl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclopropylmethyl) -2-methyl-4- (1- (4- (trifluoromethyl) phenyl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclopropylmethyl) -2-methyl-4- ((4- (trifluoromethyl) phenyl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclopropylmethyl) -2-methyl-4- ((6- (trifluoromethyl) pyridin-3-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclopropylmethyl) -2-methyl-4- (1- (6- (trifluoromethyl) pyridin-3-yl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclopropylmethyl) -4- ((6-methoxypyridin-3-yl) methoxy) -2-methyl-5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclopropylmethyl) -4- (1- (6-methoxypyridin-3-yl) ethoxy) -2-methyl-5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclopropylmethyl) -2-methyl-4- ((6-methylpyridin-3-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclopropylmethyl) -2-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclopropylmethyl) -2-ethyl-4- ((6- (trifluoromethyl) pyridin-3-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclobutylmethyl) -4- ((6-methylpyridin-3-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclobutylmethyl) -4- (1- (6-methylpyridin-3-yl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclobutylmethyl) -4- (1- (6-methylpyridin-3-yl) propoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclobutylmethyl) -4- (2-methyl-1- (6-methylpyridin-3-yl) propoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclobutoxy) -4- (1- (5-methylpyridin-2-yl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclobutylmethyl) -4- (1- (p-tolyl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclobutylmethyl) -4- (1- (1-isopropyl-1H-pyrazol-4-yl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
4- (1- ((6- (cyclobutylmethyl) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidin-4-yl) oxy) ethyl) -3,5-dimethylisoxazole;
2- (cyclobutylmethyl) -8- (1- (6-methylpyridin-3-yl) ethoxy) -1,2,3,4-tetrahydro-2,7-naphthyridine;
2- (cyclobutylmethyl) -8- (1- (5-methylpyridin-2-yl) ethoxy) -1,2,3,4-tetrahydro-2,7-naphthyridine;
6- (Cyclobutylmethyl) -4- ((6-trifluoromethylpyridin-3-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] -pyrimidine.
In another aspect, the present invention provides a pharmaceutical composition, comprising a compound of formula IA or I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In another aspect, the present invention provides the use of a compound of formula IA or I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the invention, in the manufacture of a medicament for the treatment and/or prevention of a sigma receptor related disease or condition; preferably, the sigma receptor-related disease is a central nervous system disease; more preferably, the central nervous system disorder is depression, anxiety or bipolar disorder.
In another aspect of the present invention, there is provided a process for the preparation of a compound of formula IA, comprising the steps of:
scheme 1: reacting compound II or a salt thereof with R 1a -X 1 Obtaining an intermediate III 'by substitution reaction, and then reacting the intermediate III' with
Figure BDA0003607425300000071
Or a salt thereof is subjected to a ring closure reaction and converted into an intermediate IV ', the intermediate IV' is subjected to a halogenation reaction to obtain an intermediate V ', and the intermediate V' is reacted with
Figure BDA0003607425300000072
Conversion to a compound of formula IA by a substitution reaction:
Figure BDA0003607425300000073
wherein W is N, X 1 、X 2 Independently selected from Cl, br or I, R 1a 、R 2a 、R 3a 、R 4a As defined above.
Scheme 2: reacting a compound IAa with
Figure BDA0003607425300000074
Reacting, converting into a compound IAb, and then performing reduction reaction to obtain a compound IAc, and converting the compound IAc into a compound IA by substitution reaction or ammoniation reduction reaction:
Figure BDA0003607425300000075
wherein W is CH, X 1 Is halogen, R 1a 、R 2a 、R 3a 、R 4a As defined above.
Further, scheme 1: preferably, compound II is reacted with halogenated R in a suitable solvent (e.g., acetonitrile, ethyl acetate, etc.) under basic conditions (e.g., triethylamine, sodium methoxide, sodium ethoxide, sodium carbonate, etc.) 1a (preferably R) 1 -Br) to obtain intermediate III, ring-closing reaction of intermediate III with alkyl amidine acetate in proper solvent (methanol, ethanol, etc.), and reaction with carbon tetrachloride in DCE solvent under catalysis of triphenylphosphine to obtain compound V
Figure BDA0003607425300000076
The conversion to compound I by substitution under strongly basic (e.g. NaH) conditions is as follows:
Figure BDA0003607425300000081
further, said scheme 2, preferably the compound IAa with
Figure BDA0003607425300000082
Reacting in a suitable solvent (such as DMF) under the condition of strong base (such as NaH) to convert into IAb, and then reacting under the conditions of sodium borohydride and acetic acid to obtain IAc; compound IAc and halogenated R 1a (e.g., cl-R) 1a ) Converted to compound IA by a substitution reaction, or compound IAc is first aminated with the corresponding aldehyde and then reduced with a reducing agent (preferably sodium borohydride triacetate) to give compound IA.
In another aspect, an intermediate compound is provided having the structure:
Figure BDA0003607425300000083
wherein R is 9 Is halogen or hydroxy, R 2c Is H, halogen, C 1-5 Alkyl radical, C 1-5 Haloalkyl or C 1-5 An alkoxy group; preferably R 2c Is H, R 9 Is Cl, br or hydroxyl;
Figure BDA0003607425300000084
wherein R is 2d Is hydrogen, halogen, C 1-5 Alkyl radical, C 1-5 Haloalkyl or C 1-5 Alkoxy, preferably H, methyl or ethyl;
Figure BDA0003607425300000085
wherein R is 2e Is halogen, C 1-5 Alkyl radical, C 1-5 Haloalkyl orC 1-5 Alkoxy, preferably methyl or ethyl;
Figure BDA0003607425300000091
wherein R is 2f Is hydrogen, halogen, C 1-5 Alkyl radical, C 1-5 Haloalkyl or C 1-5 Alkoxy, preferably H, methyl or ethyl.
In another aspect, the invention also provides the use of the above intermediate compounds IVb, IVc, IVd, IVe in the preparation of compounds of formula I or IA.
Detailed Description
The terms "optional," "optionally," or "optionally present" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "an optionally present bond" means that the bond may or may not be present, and the description includes single, double, or triple bonds, and the like.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements. It is to be understood that the term "comprising" can encompass the closed meaning, i.e., "consisting of …".
As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as compounds of the general formula above or as specified in the examples, subclasses. It is understood that the term "optionally substituted with one or more substituents" can be used interchangeably with the term "substituted or unsubstituted. In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optionally substituted group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be substituted at each position, identically or differently.
In addition, it should be noted that, unless otherwise explicitly indicated, the description as used herein is intended to be interpreted broadly, and it may mean that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges.
The straight-chain or branched alkyl groups described in the present invention are selected from C 1-8 The "C1-8 alkyl group" includes a straight-chain or branched-chain alkyl group having 1 to 8 carbon atoms, and particularly refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl.
“C 1-5 Alkyl "defines straight and branched chain saturated hydrocarbon groups having 1 to 5 carbon atoms, for example: methyl, ethyl, propyl, butyl, pentyl, 1-methylbutyl, 2,2-dimethylpropyl, 2,2-dimethylethyl, and the like.
C 1-8 Alkyl defines straight and branched chain saturated hydrocarbon groups having from 1 to 8 carbon atoms and includes C1-7 alkyl and its higher homologs having 8 carbon atoms such as: 2,3-dimethylhexyl, 2,3,4-trimethylpentyl, and the like;
the "cycloalkyl" is an alicyclic hydrocarbon. Typical cycloalkyl groups contain 1 to 4 monocyclic and/or fused rings and 3 to about 18 carbon atoms, preferably 3 to 7 carbon atoms, C 3-7 Cycloalkyl groups are typically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like;
the "haloalkyl" refers to an alkyl substituted with at least one halogen, preferably the haloalkyl is C 1-5 Haloalkyl of said "C 1-5 By haloalkyl "is meant C 1-5 Alkyl radicals in which one or more hydrogens of the alkyl radical have been replaced by halogen, e.g. trifluoromethyl (-CF) 3 ) Trifluoroethyl (-CH) 2 CF 3 ) Difluoromethyl (-CHF) 2 ) Fluoromethyl (-CH) 2 F) Chloromethyl radical(-CH 2 Cl), chloroethyl (-CH) 2 CH 2 Cl), and the like.
The "alkoxy" is preferably C 1-5 Examples of the alkoxy group of (a) include: methoxy, ethoxy, propoxy, butoxy, 1-methylethoxy, 2-methylpropoxy, and the like.
The six-membered aromatic ring refers to an aromatic ring having 6 ring atoms, specifically a benzene ring. The six-membered aromatic heterocyclic ring refers to a six-membered aromatic ring such as pyridine, pyridazine and the like, in which one or more CH is substituted by N, O or S on the benzene ring, and the five-membered aromatic heterocyclic ring refers to a five-membered aromatic ring containing one or more hetero atoms such as N, O or S, such as furyl, pyrrolyl, pyrazolyl or isoxazolyl and the like. The five-membered aromatic heterocyclic ring or the six-membered aromatic heterocyclic ring includes all possible isomer forms thereof. For example: pyrrolyl also includes 2H-pyrrolyl. The phenyl, pyridine, pyridazine, furan, pyrrole, pyrazole, or isoxazole may be optionally substituted with one or more substituents independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, pentyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, monofluoroethyl, fluoro, chloro, bromo, and the like.
Halogen means fluorine, chlorine, bromine and iodine.
Figure BDA0003607425300000101
Represents a substituent attachment position.
Reference herein to pharmaceutically acceptable salts is to therapeutically active, non-toxic acid addition salt forms which the compounds of formula IA or I are capable of forming. The latter can be conveniently obtained by treating the basic form with a suitable acid. Suitable acids include, for example, inorganic acids, such as hydrohalic acids, e.g., hydrochloric or hydrobromic acid; sulfuric acid, nitric acid, phosphoric acid, and the like; organic acids such as acetic acid, propionic acid, hydroxyacetic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid (i.e., butane-diacid), maleic acid, malic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylalkylamine sulfonic acid (cyclamic acid), salicylic acid, p-aminosalicylic acid and the like.
The term addition salt as used above also comprises the solvates which the compounds of formula IA or I and their pharmaceutically acceptable salts are able to form. Such solvates as hydrates, alcoholates and the like.
Compounds of formula IA or I and pharmaceutically acceptable salts thereof also include those which may possess different isomeric and conformational forms. Unless otherwise indicated or indicated, the chemical designation of compounds denotes the mixture of all possible stereoisomeric and conformational isomeric forms, said mixture comprising the basic molecular structure and all its diastereomers, enantiomers and/or conformational isomers. All stereoisomeric forms of the compounds of formula IA or I, in pure form or in admixture with each other, are intended to be included within the scope of the present invention.
Some compounds of formula IA or I may also exist in tautomeric forms. Such forms, while not explicitly indicated in the above form, are intended to be included within the scope of the present invention.
The compounds of formula I or IA according to the invention or a pharmaceutically acceptable salt thereof, to which one or more of the following restrictions apply: has a structure represented by the following formula I-1 or I-2:
Figure BDA0003607425300000111
R 1 ' is independently selected from substituted or unsubstituted straight or branched C 1-8 Alkyl of (C) 3-7 Said substituents being selected from halogen, C 1-5 Alkyl of (C) 3-7 Cycloalkyl groups of (a);
R 2 ' is independently selected from hydrogen, halogen, substituted or unsubstituted straight or branched C 1-5 Alkyl of (C) 1-5 The substituents are selected from halogen;
R 3 ' is independently selected from hydrogen, straight or branched chain C 1-5 Any one of alkyl groups of (a);
R 5 ' is independently selected from halogen, optionally substituted straight or branched C 1-8 Alkyl of (C) 1-5 Wherein the optional substitution may be mono-, di-, poly-or unsubstituted.
R 6 ' absent or independently selected from optionally substituted straight or branched C 1-8 Alkyl of (C) 1-5 The substituent is selected from halogen, and the optional substitution can be mono-substitution, di-substitution, multi-substitution or non-substitution.
R 7 ' independently selected from hydrogen, straight or branched C 1-5 Any one of the alkyl groups of (a);
R 8 ' independently selected from hydrogen, straight or branched C 1-5 Any one of the alkyl groups of (a);
A 1 、A 2 、A 4 independently selected from any one of N, C;
A 3 independently selected from any one of N, C or O; and A is 3 、A 4 Not simultaneously C.
In a further aspect of the present invention,
R 1 ' is independently selected from straight or branched chain C 1-5 The alkyl group of (a) is,
Figure BDA0003607425300000112
wherein n1 and n2 are integers of 1-5.
Further, in the above-mentioned case,
R 1 ' is independently selected from methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, and mixtures thereof,
Figure BDA0003607425300000121
Wherein n1 and n2 are independently integers of 1-5;
R 2 ' is independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, trifluoromethyl, difluoromethyl, difluoroethyl, monofluoromethyl, monofluoroethyl;
R 3 ' is independently selected from any one of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and pentyl;
R 5 ' is independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, difluoroethyl, monofluoromethyl, monofluoroethyl;
R 6 ' absent or independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, difluoroethyl, monofluoromethyl, monofluoroethyl;
R 7 ' is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl;
R 8 ' is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl;
A 1 、A 2 、A 4 independently selected from any one of N, C;
A 3 independently selected from any one of N, C or O; and A is 3 、A 4 Not being C at the same time.
Further, the straight chain or branched chain alkyl in the structures of the formulas I, I-1 and I-2 is selected from C 1-5 Linear or branched alkyl of (a); said cycloalkyl group is selected from C 3-7 Cycloalkyl groups of (a); the alkyl substituted by at least one halogen is selected from C substituted by at least one halogen 1-5 Alkyl group of (1).
Furthermore, in the structures of the formulas I, I-1 and I-2, the halogen is selected from any one of fluorine, chlorine, bromine or iodine.
Further, in the structures of the above formulas I, I-1 and I-2, C is 1-5 The straight chain or branched chain alkyl of (2) is any one of methyl, ethyl, propyl, butyl and pentyl; said C is 3-7 The cycloalkyl of (A) is any one of cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; said C substituted by at least one halogen 1-5 The alkyl group of (b) is any one of a trifluoromethyl group and a difluoromethyl group. In one embodiment of the invention, the propyl group includes, but is not limited to, n-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Or isopropyl (i-Pr, -CH (CH) 3 ) 2 ) (ii) a The butyl group includes, but is not limited to, n-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) Or tert-butyl (t-Bu, -C (CH) 3 ) 3 ) (ii) a Said pentyl group includes but is not limited to n-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) Or 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 )。
Straight or branched chain C of the invention 1-8 The alkyl of (a) is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isopentyl, isobutyl;
Figure BDA0003607425300000131
wherein n1 is an integer of 1,2,3,4, 5, and n2 is an integer of 1,2,3,4, 5;
Figure BDA0003607425300000132
specifically cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl; cyclopropylethyl, cyclo Ding Yiji, cyclopentylethyl, cyclohexylethyl; cyclopropyl, ring Ding Bingji, cyclopentylpropyl, cyclohexylpropyl.
C 1-5 The alkoxy is methoxy, ethoxy, propoxy or butoxy.
The invention has the beneficial technical effects that:
the 5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine-4-alcohol derivative provided by the invention is a sigma-1 receptor agonist with a brand-new structure; has obvious binding force to sigma-1 receptor and has good application prospect in the field of treating and preventing central nervous system diseases.
TABLE 1 exemplary Compounds of the general formulae IA, I-1, I-2
Figure BDA0003607425300000133
Figure BDA0003607425300000141
Figure BDA0003607425300000151
Figure BDA0003607425300000161
Examples
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention.
The compounds and compositions of the present invention may be used with other drugs to provide combination therapy. The other agents may form part of the same composition, or as separate compositions for simultaneous or non-simultaneous administration. The following examples are given solely for the purpose of further illustrating the invention and should not be taken as limiting the scope of the invention. The compounds of the following examples were prepared using the general formula IA synthesis described in scheme 1 above.
Example 1:6- (Cyclobutylmethyl) -4- (1- (6- (trifluoromethyl) pyridin-3-yl) ethoxy) -5,6,7,8-Tetrahydropyrido [4,3-d]And (3) preparing pyrimidine.
Figure BDA0003607425300000162
1.1 Preparation of 1- (cyclobutylmethyl) -4-oxypiperidine-3-carbonic acid ethyl ester
Figure BDA0003607425300000171
Dissolving 4-oxypiperidine-3-carboxylic acid ethyl ester hydrochloride (2.08g, 10mmol), bromomethylcyclobutane (1.79g, 12mmol) and triethylamine (1.21g, 12mmol) in acetonitrile (40 mL), stirring at 0-20 ℃ for reaction overnight, monitoring the completion of the raw material reaction by TLC, filtering and concentrating to obtain a crude product, and purifying the crude product by column chromatography (DCM/MeOH = 10/1) to obtain 1- (cyclobutylmethyl) -4-oxypiperidine-3-carboxylic acid ethyl ester (1.70 g, yield 71.2%).
1.2 Preparation of 6- (cyclobutylmethyl) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidin-4-ol
Figure BDA0003607425300000172
Dissolving 1- (cyclobutylmethyl) -4-oxypiperidine-3-carboxylic acid ethyl ester (1.50g, 6.27mmol), formamidine acetate (0.78g, 7.52mmol) and sodium ethoxide (0.94g, 13.79mmol) in ethanol (30 mL), heating the reaction solution in an oil bath to 75 ℃, stirring and reacting overnight, monitoring the completion of the reaction by TLC, concentrating the reaction solution to remove the organic solvent, adding 30mL of aqueous sodium hydroxide (0.5 mol/L) to dissolve and clarify the reaction solution, adding 30mL of methyl tert-butyl ether to extract, adjusting the pH of the separated aqueous phase to 6-7 with 50% aqueous glacial acetic acid, extracting with dichloromethane (40mL x 3), combining the organic layers, washing with saturated NaCl (3 x 20mL), drying with anhydrous sodium sulfate, filtering, and concentrating to obtain crude 6- (cyclobutylmethyl) -5,6,7,8-tetrahydropyridol [4,3-d ] pyrimidine-4-ol (0.89 g, 64.5%).
1.3 Preparation of 4-chloro-6- (cyclobutylmethyl) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine
Figure BDA0003607425300000173
6- (Cyclobutylmethyl) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidin-4-ol (0.87g, 3.97mmol), triphenylphosphine (2.08g, 7.94mmol), carbon tetrachloride (1.22g, 7.94mmol) were dissolved in 1,2-dichloroethane (40 mL) and the oil bath was heated to reflux and stirred for reaction overnight. The reaction solution was monitored by TLC for completion of the reaction of the starting materials, quenched with water (50 mL), extracted with dichloromethane (50mL. Times.3), combined organic layers, washed with saturated NaCl (20mL. Times.3), dried over anhydrous sodium sulfate, filtered, concentrated to give crude product, and purified by column chromatography (PE: EA =0% -50%) to give pure 4-chloro-6- (cyclobutylmethyl) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine (0.65 g, yield: 65.2%).
1.4: preparation of 6- (cyclobutylmethyl) -4- (1- (6- (trifluoromethyl) pyridin-3-yl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine
Figure BDA0003607425300000181
1- (6- (trifluoromethyl) pyridin-3-yl) ethyl-1-ol (0.19g, 1mmol) and tetrahydrofuran (10 ml) were stirred at-10 ℃ for 10 minutes, naH (44mg, 1, 1mmol) was added, then reaction was stirred at-10 ℃ for 60 minutes, and 4-chloro-6- (cyclobutylmethyl) -5,6,7,8-tetrahydropyrido [4,3-d ] was added]Pyrimidine (0.24g, 1mmol) was reacted with stirring at 20 ℃ for 6h. The reaction solution was monitored by TLC for completion of the reaction, quenched with water (50 mL), extracted with ethyl acetate (3X 50mL), combined organic layers, washed with saturated NaCl (3X 20mL), dried over anhydrous sodium sulfate, filtered, concentrated to give crude product, which was subjected to preparative-TLC (DCM: meOH: NH) 3 .H 2 O =20:1:0.1 Separation and extraction of 6- (cyclobutylmethyl) -4- (1- (6- (trifluoromethyl) pyridin-3-yl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d]Pure pyrimidine (0.21 g, yield: 54.2%).
1H NMR(400MHz,Methanol-d4)δ8.89–8.73(m,2H),8.22–8.09(m,1H),7.78(m,1H),6.51(m,1H),4.69-4.10(m,2H),3.96-3.65(m,1H),3.55–3.35(m,3H),3.25–3.07(m,2H),2.92(m,1H),2.21(m,2H),2.01(m,1H),1.94–1.84(m,3H),1.75(m,3H).MS(ESI)m/z:393[M+1]。
Example 3236 preparation of zxft 3236- (cyclopropylmethyl) -2-methyl-4- (1- (4- (trifluoromethyl) phenyl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine.
Figure BDA0003607425300000182
Preparation of 6- (cyclopropylmethyl) -2-methyl-4- (1- (4- (trifluoromethyl) phenyl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine reference example 1.
1H NMR(400MHz,Methanol-d4)δ7.78–7.69(m,4H),6.59(q,J＝6.5Hz,1H),4.79–4.30(m,2H),4.19-3.88(m,1H),3.78–3.45(m,2H),3.45-3.34(m,3H),2.71(s,,3H),1.80(d,J＝6.6Hz,3H),1.40-1.32(m,1H),0.91–0.82(m,2H),0.63–0.53(m,2H).MS(ESI)m/z:392[M+1]。
Example 3236 preparation of zxft 3236- (cyclopropylmethyl) -2-methyl-4- ((4- (trifluoromethyl) phenyl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine
Figure BDA0003607425300000183
Preparation of 6- (cyclopropylmethyl) -2-methyl-4- ((4- (trifluoromethyl) phenyl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine reference example 1.
1H NMR(400MHz,Methanol-d4)δ7.68-7.60(m,4H),5.67(s,2H),4.64–4.25(m,2H),4.12-3.86(m,2H),3.48-3.38(m,3H),2.67(s,3H),2.52-2.46(m,1H),1.19–1.16(m,1H),0.78-0.66(m,2H),0.43(d,J＝5.7Hz,2H).MS(ESI)m/z:378[M+1]。
Example preparation of 4:6- (cyclopropylmethyl) -2-methyl-4- ((6- (trifluoromethyl) pyridin-3-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine.
Figure BDA0003607425300000191
Preparation of 6- (cyclopropylmethyl) -2-methyl-4- ((6- (trifluoromethyl) pyridin-3-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine reference example 1.
1H NMR(400MHz,Methanol-d4)1H NMR(400MHz,Methanol-d4)δ8.90(s,1H),8.24-8.22(m,1H),7.87-7.85(m,1H),5.68(s,2H),4.86-4.38(m,2H),4.04-3.34(m,2H),3.32-3.30(m,4H),2.70(s,3H),1.30(m,1H),0.87-0.85(m,2H),0.57-0.56(m,2H).MS(ESI)m/z:379[M+1]。
Example 3236 preparation of zxft 3236- (cyclopropylmethyl) -2-methyl-4- (1- (6- (trifluoromethyl) pyridin-3-yl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine
Figure BDA0003607425300000192
Preparation of 6- (cyclopropylmethyl) -2-methyl-4- (1- (6- (trifluoromethyl) pyridin-3-yl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine reference example 1.
1H NMR(400MHz,Methanol-d 4 )δ8.90(s,1H),8.24-8.22(m,1H),7.87-7.85(m,1H),6.66-6.61(m,1H),4.86-4.38(m,2H),4.04-3.34(m,2H),3.32-3.30(m,4H),2.70(s,3H),1.84-1.83(m,3H),1.30(m,1H),0.87-0.85(m,2H),0.57-0.56(m,2H).MS(ESI)m/z:393[M+1]。
Example 3236 preparation of zxft 3236- (cyclopropylmethyl) -4- ((6-methoxypyridin-3-yl) methoxy) -2-methyl-5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine.
Figure BDA0003607425300000193
Preparation of 6- (cyclopropylmethyl) -4- ((6-methoxypyridin-3-yl) methoxy) -2-methyl-5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine reference example 1.
1H NMR(400MHz,Methanol-d 4 )δ8.50(m,1H),8.42(m,1H),7.37(m,1H),5.71(s,2H),4.62-4.56(m,1H),4.36(m,1H),4.10(s,3H),4.02(m,1H),3.61–3.40(m,2H),3.26(m,3H),2.76(s,3H),1.16(m,1H),0.75(m,2H),0.48(m,2H).MS(ESI)m/z:340[M+1]。
Example 3236 preparation of zxft 3236- (cyclopropylmethyl) -4- (1- (6-methoxypyridin-3-yl) ethoxy) -2-methyl-5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine.
Figure BDA0003607425300000201
Preparation of 6- (cyclopropylmethyl) -4- (1- (6-methoxypyridin-3-yl) ethoxy) -2-methyl-5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine reference example 1.LCMS: [ M +1] =354.
Example preparation of 8:6- (cyclopropylmethyl) -2-methyl-4- ((6-methylpyridin-3-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine.
Figure BDA0003607425300000202
Preparation of 6- (cyclopropylmethyl) -2-methyl-4- ((6-methylpyridin-3-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine reference example 1.LCMS: m +1] =325.
Example 3236 preparation of zxft 3236- (cyclopropylmethyl) -2-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine.
Figure BDA0003607425300000203
Preparation of 6- (cyclopropylmethyl) -2-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine reference example 1.LCMS: [ M +1] =379.
Example 10 preparation of 6- (cyclopropylmethyl) -2-ethyl-4- ((6- (trifluoromethyl) pyridin-3-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine
Figure BDA0003607425300000204
Preparation of 6- (cyclopropylmethyl) -2-ethyl-4- ((6- (trifluoromethyl) pyridin-3-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine reference example 1.
1H NMR(400MHz,Methanol-d 4 )δ8.93–8.78(m,1H),8.24–8.10(m,1H),7.85(m,1H),5.68(s,2H),3.74(s,2H),3.03(m,2H),2.94(m,2H),2.81(m,2H),2.59(m,2H),1.29(t,J＝7.6Hz,3H),1.03(m,1H),0.71–0.55(m,2H),0.26(m,2H)。MS(ESI)m/z:393[M+1]。
Example 11 preparation of 6- (cyclobutylmethyl) -4- ((6-methylpyridin-3-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine
Figure BDA0003607425300000211
Preparation of 6- (cyclobutylmethyl) -4- ((6-methylpyridin-3-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine reference example 1.
1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝6.5Hz,2H),7.69(d,J＝8.1Hz,1H),7.21(d,J＝8.0Hz,1H),5.36(s,2H),3.30(s,2H),2.82-2.66(m,2H),2.63-2.56(m,2H),2.47-2.44(m,J＝5.3Hz,3H),2.40(s,3H),2.04-1.89(m,2H),1.86–1.67(m,2H),1.65-1.51(m,2H).MS(ESI)m/z:325[M+1]。
Example 12: preparation of 6- (cyclobutylmethyl) -4- (1- (6-methylpyridin-3-yl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine.
Figure BDA0003607425300000212
Preparation of 6- (cyclobutylmethyl) -4- (1- (6-methylpyridin-3-yl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine reference example 1.
1H NMR(400MHz,DMSO-d6)δ8.47(d,J＝2.4Hz,1H),8.47(s,1H),7.78-7.68(m,1H),7.20(d,J＝8.0Hz,1H),6.25(q,J＝6.5Hz,1H),3.48-3.34(m,2H),2.74-2.68(m,2H),2.65-2.62(m,2H),2.54-2.50(m,3H),2.43(s,3H),2.08-1.94(m,2H),1.91–1.74(m,2H),1.68-1.61(m,2H),1.58(d,J＝6.5Hz,3H).MS(ESI)m/z:339[M+1]。
Example 13: preparation of 6- (cyclobutylmethyl) -4- (1- (6-methylpyridin-3-yl) propoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine
Figure BDA0003607425300000213
Preparation of 6- (cyclobutylmethyl) -4- (1- (6-methylpyridin-3-yl) propoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine reference example 1.
1H NMR(400MHz,DMSO-d6)δ8.47(d,J＝2.4Hz,1H),8.43(s,1H),7.70-7.63(m,1H),7.21(d,J＝8.0Hz,1H),6.04(q,J＝6.5Hz,1H),3.38(d,J＝9.6Hz,2H),2.73-2.68(m,2H),2.65-2.62(m,2H),2.54-2.50(m,3H),2.39(s,3H),2.06-1.92(m,2H),1.89–1.72(m,2H),1.68-1.61(m,2H),1.55(d,J＝6.5Hz,3H),0.92-0.81(m,3H).MS(ESI)m/z:353[M+1]。
Example 14: preparation of 6- (cyclobutylmethyl) -4- (2-methyl-1- (6-methylpyridin-3-yl) propoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine
Figure BDA0003607425300000221
Preparation of 6- (cyclobutylmethyl) -4- (2-methyl-1- (6-methylpyridin-3-yl) propoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine reference example 1.
1H NMR(400MHz,DMSO-d6)δ8.42(d,J＝2.2Hz,1H),8.40(s,1H),7.62(dd,J＝8.0,2.3Hz,1H),7.21(d,J＝8.0Hz,1H),5.90(d,J＝6.6Hz,1H),3.50(s,2H),2.78-2.66(m,4H),2.64–2.56(m,3H),2.42(s,3H),2.54-2.14(m,1H),2.11-2.01(m,2H),1.95–1.78(m,2H),1.76-1.64(m,2H),0.95(d,J＝6.7Hz,3H),0.85(d,J＝6.7Hz,3H).MS(ESI)m/z:367[M+1]。
Example 15: preparation of 6- (cyclobutoxy) -4- (1- (5-methylpyridin-2-yl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine
Figure BDA0003607425300000222
Preparation of 6- (cyclobutoxy) -4- (1- (5-methylpyridin-2-yl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine reference example 1.
1H NMR(401MHz,DMSO-d6)δ8.69(d,J＝5.7Hz,1H),8.60(s,1H),8.26(d,J＝8.1Hz,1H),7.94(dd,J＝15.4,8.2Hz,1H),6.45(t,J＝6.8Hz,1H),4.40-4.38(m,2H),3.69-3.59(m,1H),3.40-3.30(m,4H),3.00-2.94(m,2H),2.43(s,3H),2.21-2.09(m,2H),1.92–1.79(m,4H),1.73(dd,J＝6.7,3.8Hz,3H).MS(ESI)m/z:339[M+1]。
Example 16: preparation of 6- (cyclobutylmethyl) -4- (1- (p-tolyl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine
Figure BDA0003607425300000223
Preparation of 6- (cyclobutylmethyl) -4- (1- (p-tolyl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine reference example 1.
1H NMR(401MHz,DMSO-d6)δ8.54(s,1H),7.31(d,J＝7.8Hz,2H),7.16(d,J＝7.8Hz,2H),6.28–6.20(m,1H),3.82-3.86(m,2H),3.17-3.10(m,2H),2.99(d,J＝7.1Hz,2H),2.95-2.87(m,2H),2.76–2.68(m,1H),2.27(s,3H),2.08(q,J＝9.3,8.1Hz,2H),1.93-1.86(m,1H),1.80(q,J＝8.5,7.4Hz,3H),1.57(d,J＝6.5Hz,3H).MS(ESI)m/z:338[M+1]。
Example 18: preparation of 4- (1- ((6- (cyclobutylmethyl) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidin-4-yl) oxy) ethyl) -3,5-dimethylisoxazole
Figure BDA0003607425300000231
Preparation of 4- (1- ((6- (cyclobutylmethyl) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidin-4-yl) oxy) ethyl) -3,5-dimethylisoxazole, reference example 1.
1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),6.14(q,J＝6.7Hz,1H),3.46–3.34(m,2H),2.77–2.71(m,2H),2.70-2.62(m,2H),2.57-2.53(m,3H),2.44(s,3H),2.30(s,3H),2.07-2.00(m,2H),1.92–1.76(m,2H),1.73-1.64(m,2H),1.59(d,J＝6.7Hz,3H).MS(ESI)m/z:343[M+1]。
Example 21: preparation of 6- (cyclobutylmethyl) -4- ((6-trifluoromethylpyridin-3-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] -pyrimidine
Figure BDA0003607425300000232
Preparation of 6- (cyclobutylmethyl) -4- ((6-trifluoromethylpyridin-3-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] -pyrimidine reference example 1.
1H NMR(401MHz,DMSO-d6)δ8.82(s,1H),8.55(s,1H),7.92(dd,J＝16.0,8.0Hz,1H),7.56(d,J＝8.0Hz,1H),5.54(s,2H),3.50(s,2H),2.94-2.91(m,2H),2.78-2.75(m,2H),2.63-2.61(m,2H),2.94-2.91(m,2H),2.13-2.09(m,2H),1.92-1.84(m,2H),1.76-1.71(m,2H)；MS(ESI)m/z:378[M+1]。
Using the general formula IA synthesis described in scheme 2 above, the compound of example 19,20 was prepared
Example 19: preparation of 2- (cyclobutylmethyl) -8- (1- (6-methylpyridin-3-yl) ethoxy) -1,2,3,4-tetrahydro-2,7-naphthyridine
Figure BDA0003607425300000233
(1) Preparation of 1- (1- (6-methylpyridin-3-yl) ethoxy) -2,7-naphthyridine
Figure BDA0003607425300000234
Sequentially adding 2,7-naphthyridine-1-hydroxy (292mg, 2.0mmol) and DMF (10 ml) into a reaction bottle, and stirring and reacting at-10 ℃ for 10min under the protection of nitrogen; then NaH (96mg, 1.2mmol) is slowly added, the reaction is stirred at the temperature of minus 10 ℃ for 1h, then 5- (1-chloroethyl) -2-methylpyridine (313mg, 2.0 mmol) is added, after the addition is finished, the temperature is slowly increased to 20 ℃, and the reaction is stirred at the temperature for 2h; the reaction was quenched by TLC, the reaction was quenched by addition of water (40 ml), extracted with ethyl acetate (3 × 40ml), dried over anhydrous sodium sulfate and concentrated to give a crude colorless oil.
(2) Preparation of 8- (1- (6-methylpyridin-3-yl) ethoxy) -1,2,3,4-tetrahydro-2,7-naphthyridine
Figure BDA0003607425300000241
Dissolving the crude product 1- (1- (6-methylpyridin-3-yl) ethoxy) -2,7-naphthyridine obtained in the last step in glacial acetic acid (10 ml), stirring and reacting at-10 ℃ for 10min under the protection of nitrogen, slowly adding sodium borohydride (76mg, 2.0mmol), and stirring and reacting at-10 ℃ for 1h; after TLC monitoring reaction, adding water (40 ml) into the reaction solution for quenching, extracting by dichloromethane (2 × 40ml), combining organic phases, drying by anhydrous sodium sulfate, and concentrating to obtain a colorless oily crude product; column chromatography, eluent: meOH: DCM =0% -8% to give 130mg of light yellow oil.
(3) Preparation of 2- (cyclobutylmethyl) -8- (1- (6-methylpyridin-3-yl) ethoxy) -1,2,3,4-tetrahydro-2,7-naphthyridine
Figure BDA0003607425300000242
Dissolving the crude product 8- (1- (6-methylpyridin-3-yl) ethoxy) -1,2,3,4-tetrahydro-2,7-naphthyridine, ring Ding Jiaquan (84mg, 1.01mmol) and glacial acetic acid (2 drops) obtained in the last step into dichloromethane (20 ml), stirring and reacting for 1h at 20 ℃, cooling the reaction liquid to 0 ℃, stirring for 10min, then adding sodium borohydride acetate (212mg, 1.01mmol), heating to 20 ℃, and stirring and reacting for 6h; TLC monitoring reaction is finished, saturated sodium bicarbonate solution (40 ml) is added to quench the reaction, dichloromethane (3 × 40ml) is used for extraction, organic phases are combined, anhydrous sodium sulfate is used for drying, and light yellow oily crude product is obtained by concentration; and (3) carrying out column chromatography on the crude product, and eluting the eluent: meOH: DCM =0% -6% to give 2- (cyclobutylmethyl) -8- (1- (6-methylpyridin-3-yl) ethoxy) -1,2,3,4-tetrahydro-2,7-naphthyridine (150 mg) as a light yellow oil.
1H NMR(401MHz,DMSO-d6)δ8.48(d,J＝2.3Hz,1H),7.80(d,J＝5.2Hz,1H),7.68(dd,J＝8.1,2.4Hz,1H),7.21(d,J＝8.0Hz,1H),6.69(d,J＝5.2Hz,1H),6.19(q,J＝6.5Hz,1H),3.47–3.37(m,2H),2.75-2.65(m,2H),2.61-2.51(m,5H),2.42(s,3H),2.08–1.98(m,2H),1.93–1.77(m,2H),1.68(p,J＝8.7Hz,2H),1.55(d,J＝6.5Hz,3H).MS(ESI)m/z:338[M+1]。
Example 20: preparation of 2- (cyclobutylmethyl) -8- (1- (5-methylpyridin-2-yl) ethoxy) -1,2,3,4-tetrahydro-2,7-naphthyridine
Figure BDA0003607425300000251
Preparation of 2- (cyclobutylmethyl) -8- (1- (5-methylpyridin-2-yl) ethoxy) -1,2,3,4-tetrahydro-2,7-naphthyridine, reference example 19.
1H NMR(401MHz,DMSO-d6)δ8.35(s,1H),7.70(d,J＝5.2Hz,1H),7.56(dd,J＝8.1,2.4Hz,1H),7.26(d,J＝8.0Hz,1H),6.69(d,J＝5.2Hz,1H),6.14(q,J＝6.5Hz,1H),3.48-3.41(m,2H),2.75-2.71(m,2H),2.69–2.48(m,5H),2.25(s,3H),2.08-1.96(m,2H),1.94–1.77(m,2H),1.76-1.62(m,2H),1.54(d,J＝6.5Hz,3H).MS(ESI)m/z:338[M+1]。
Pharmacological examples:
representative compounds of the invention were tested for activity as sigma-1 agonists, and the specific protocol was as follows:
test Compound preparation: DMSO was dissolved at a final concentration of 1% in all test samples, and HCl (10%, 10. Mu.L) was added as appropriate at an initial concentration of 1.0X 10 -5 M (i.e., 10. Mu.M), then 1. Mu.M, 333nM, 100nM, 33nM, 10nM, 3.3nM, 1nM, 0.33nM, 0.1nM, 0.01nM, in that order.
Sigma-1 binding activity assay:
receptor membrane preparation: homogenizing guinea pig whole brain with 10mM Tris-HCl buffer solution containing 320mM sucrose pH =7.4, adjusting weight, centrifuging for 10min at 1000g, collecting supernatant, adding 10mM Tris-HCl buffer solution containing sucrose pH =7.4, homogenizing, centrifuging for 10min at 1000g and 4 deg.C, collecting supernatant, centrifuging for 25min at 50000g and 4 deg.C, collecting precipitate, adding 10mM Tris-HC buffer solution containing no sucrose pH =7.4, homogenizing at 50000g and 4 deg.C, centrifuging for 25min, collecting precipitate, repeating the above operation, and storing the precipitate at-80 deg.C for use.
Binding assay: prepared acceptor membranes were made into a 220mg/ml membrane suspension with 10mM Tris-HCl buffer without sucrose pH =7.4 and ready for use. Each reaction tube was filled with 100. Mu.L of the membrane preparation. Total binding tubes 100. Mu.L of 10mM Tris-HC buffer without sucrose pH =7.4 was added to total binding Tubes (TB) and 100. Mu.L haloperidol (final concentration 1.0X 10) was added to non-specific binding tubes (NB) -5 M), 100 μ L of test compound was added to each test compound tube (CB). All reaction tubesThe radioligand 4nM [ 2 ] was added separately 3 H]10. Mu.L of Pentazocine. Incubating each reaction tube at 25 ℃ for 135min, after the reaction is finished, rapidly filtering the combined ligand through reduced pressure, soaking Whatman GF/C test paper in PEI (0.5 percent) for more than 1h in advance, fully washing the paper by using ice-cold test buffer solution, taking out a filter disc, putting the filter disc into a 4mL scintillation cup, adding 1mL of toluene scintillation solution, uniformly mixing, and finally putting the scintillation bottle into a HIDEX liquid scintillation counter for counting.
The results of the experiments are shown in Table 2 below
TABLE 2 Ki values of Compounds 1-8 for sigma receptors
Compound numbering Kiσ1nM Compound numbering Kiσ1nM
1 1.78 12 14.21
2 262.87 13 3.39
3 51.52 14 12.22
4 / 15 32.63
5 288.52 16 15.22
6 >1000 17 /
7 / 18 164.1
8 / 19 21.54
9 / 20 16.8
10 26.75 21 10.09
11 9.86
Note that: "/" indicates no activity test was performed.

Claims (17)

1. A compound of formula IA, or a pharmaceutically acceptable salt thereof:
Figure FDA0003607425290000011
wherein W is CH or N;
R 1a selected from substituted or unsubstituted straight or branched alkyl, cycloalkyl, said substituents being selected from halogen, C 1-5 Alkyl of (C) 3-7 Cycloalkyl groups of (a); (ii) a
R 2a Selected from hydrogen, halogen, alkyl, halogenated alkyl or alkoxy;
R 3a selected from hydrogen or alkyl;
R 4a is selected from six-membered aromatic ring, six-membered aromatic heterocycle and five-membered aromatic heterocycle, wherein the six-membered aromatic ring, six-membered aromatic heterocycle and five-membered aromatic heterocycle are optionally substituted by one or more substituents independently selected from hydrogen, halogen, alkyl, haloalkyl or alkoxy;
preferably R 4a Is phenyl, pyridyl, pyridazinyl, furyl, pyrrolyl, pyrazolyl or isoxazolyl optionally substituted by one or more substituents independently selected from halogen, C 1-5 Alkyl of (C) 1-5 Haloalkyl or C 1-5 Alkoxy group of (2).
2. The compound of claim 1, wherein in the compound of formula IA, W is N, and R is 4a Selected from the group Ia, ib, ic, id or Ie;
or, W is CH, and R 4a Selected from: group Ib or Ic:
Figure FDA0003607425290000012
wherein
Figure FDA0003607425290000013
Represents a substituent attachment position;
R 5a independently selected from C 1-5 Alkyl radical, C 1-5 Haloalkyl or C 1-5 Alkoxy group of (a);
R 6a independently selected from C 1-5 An alkyl group.
3. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, wherein R is 1a Independently selected from C 1-8 Alkyl radical, C 3-7 Cycloalkyl-substituted C 1-8 Alkyl radical, C 1-5 Haloalkyl or C 3-7 A cycloalkyl group;
the R is 2a Independently selected from hydrogen, halogen, C 1-5 Alkyl radical, C 1-5 Haloalkyl or C 1-5 An alkoxy group;
the R is 3a Independently selected from hydrogen or C 1-5 An alkyl group.
4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, wherein R is 1a Independently selected from cyclopropylmethyl or cyclobutylmethyl.
5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R is 2a 、R 3a Independently selected from hydrogen, methyl, ethyl or isopropyl.
6. A compound or pharmaceutically acceptable salt thereof according to any one of claims 2 to 5, wherein R is 5a Independently selected from methyl, trifluoromethyl or methoxy; r 6a Independently selected from methyl, ethyl or isopropyl.
7. A compound of formula I or a pharmaceutically acceptable salt thereof:
Figure FDA0003607425290000021
wherein
R 1 Selected from substituted or unsubstituted straight or branched alkyl, cycloalkyl, said substituents being selected from halogen, C 1-5 Alkyl of (C) 3-7 Cycloalkyl groups of (a);
R 2 selected from hydrogen, halogen, substituted or unsubstituted straight or branched alkyl, alkoxy, said substituents being selected from halogen;
R 3 any one selected from hydrogen, linear or branched alkyl;
R 4 the aromatic heterocyclic compound is selected from six-membered aromatic ring, six-membered aromatic heterocyclic ring and five-membered heterocyclic ring, wherein the six-membered aromatic ring, the six-membered aromatic heterocyclic ring and the five-membered heterocyclic ring are optionally substituted by one or more substituents, and the substituents are independently selected from any one of hydrogen, halogen, alkyl, halogenated alkyl and alkoxy.
8. The compound of claim 7, or a pharmaceutically acceptable salt thereof: wherein R is 1 Selected from substituted or unsubstituted straight or branched C 1-8 Alkyl of (C) 3-7 Said substituents being selected from halogen, C 1-5 Alkyl or C 3-7 Cycloalkyl of (a);
R 2 selected from hydrogen, halogen, straight or branched C 1-5 Alkyl of (C) 1-5 Haloalkyl or C 1-5 Alkoxy group of (a);
R 3 selected from hydrogen, straight or branched C 1-5 Any one of the alkyl groups of (a);
R 4 selected from phenyl, pyridine, pyridazine, furan, pyrrole, pyrazole or isoxazole, optionally substituted with one or more substituents, orThe substituents are independently selected from halogen and C 1-5 Alkyl of (C) 1-5 Halogenated alkyl group of (C) 1-5 Any one of the alkoxy groups of (1).
9. The compound of claim 7, or a pharmaceutically acceptable salt thereof: wherein the compound of formula I is a compound of formula I-1:
Figure FDA0003607425290000031
wherein R is 1 ' is selected from substituted or unsubstituted straight or branched C 1-8 Alkyl of (C) 3-7 Said substituents being selected from halogen, C 1-5 Alkyl of (C) 3-7 Cycloalkyl groups of (a);
R 2 ' is selected from hydrogen, halogen, C 1-5 Alkyl of (C) 1-5 Haloalkyl or C 1-5 Alkoxy group of (a);
R 3 ' is selected from hydrogen, straight or branched C 1-5 Any one of the alkyl groups of (a);
R 5 ' is selected from halogen, C 1-8 Alkyl, C substituted by one or more halogens 1-8 Alkyl or C 1-5 Alkoxy group of (a);
A 1 、A 2 independently selected from N, C or CH.
10. The compound of claim 7, or a pharmaceutically acceptable salt thereof: wherein the compound of formula I is a compound of formula I-2:
Figure FDA0003607425290000032
R 1 ' is selected from substituted or unsubstituted straight or branched C 1-8 Alkyl of (C) 3-7 Said substituents being selected from halogen, C 1-5 Alkyl of (C) 3-7 Cycloalkyl of (a);
R 2 ' is selected from hydrogen, halogen, C 1-5 Alkyl of (C) 1-5 Haloalkyl or C 1-5 Alkoxy group of (a);
R 3 ' is selected from hydrogen, straight or branched C 1-5 Any one of the alkyl groups of (a);
R 6 ' absent or selected from C 1-8 Alkyl or C substituted by one or more halogens 1-8 Alkyl groups of (a);
R 7 ' is selected from hydrogen, straight or branched C 1-5 Any one of the alkyl groups of (a);
R 8 ' is selected from hydrogen, straight or branched C 1-5 Any one of the alkyl groups of (a);
A 3 any one selected from N, C, CH or O;
A 4 any one selected from N, CH;
and A is 3 、A 4 Not simultaneously C.
11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 9 or 10, wherein R is 1 ' is independently selected from straight or branched chain C 1-5 Alkyl or
Figure FDA0003607425290000041
Wherein n1 and n2 are independently selected from integers of 1-5, more preferably, R is 1 ' is independently selected from
Figure FDA0003607425290000042
Wherein n1 is 1 and n2 is 1 or 2.
12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 9 or 10, wherein R is 2 ' is independently selected from hydrogen or C 1-5 Alkyl, more preferably hydrogen, methyl or ethyl;
the R is 3 ' independently selected from hydrogen, straight or branched C 1-5 Any one of the alkyl groups of (1)Seed growing; more preferably hydrogen, methyl, ethyl or isopropyl;
the R is 5 ' is independently selected from methyl, trifluoromethyl or methoxy.
13. The compound or pharmaceutically acceptable salt thereof according to claim 1, which is selected from any one of the following compounds:
6- (cyclobutylmethyl) -4- (1- (6- (trifluoromethyl) pyridin-3-yl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclopropylmethyl) -2-methyl-4- (1- (4- (trifluoromethyl) phenyl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclopropylmethyl) -2-methyl-4- ((4- (trifluoromethyl) phenyl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclopropylmethyl) -2-methyl-4- ((6- (trifluoromethyl) pyridin-3-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclopropylmethyl) -2-methyl-4- (1- (6- (trifluoromethyl) pyridin-3-yl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclopropylmethyl) -4- ((6-methoxypyridin-3-yl) methoxy) -2-methyl-5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclopropylmethyl) -4- (1- (6-methoxypyridin-3-yl) ethoxy) -2-methyl-5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclopropylmethyl) -2-methyl-4- ((6-methylpyridin-3-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclopropylmethyl) -2-methyl-4- ((5- (trifluoromethyl) pyridin-2-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclopropylmethyl) -2-ethyl-4- ((6- (trifluoromethyl) pyridin-3-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclobutylmethyl) -4- ((6-methylpyridin-3-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclobutylmethyl) -4- (1- (6-methylpyridin-3-yl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclobutylmethyl) -4- (1- (6-methylpyridin-3-yl) propoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclobutylmethyl) -4- (2-methyl-1- (6-methylpyridin-3-yl) propoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclobutoxy) -4- (1- (5-methylpyridin-2-yl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclobutylmethyl) -4- (1- (p-tolyl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
6- (cyclobutylmethyl) -4- (1- (1-isopropyl-1H-pyrazol-4-yl) ethoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidine;
4- (1- ((6- (cyclobutylmethyl) -5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidin-4-yl) oxy) ethyl) -3,5-dimethylisoxazole;
2- (cyclobutylmethyl) -8- (1- (6-methylpyridin-3-yl) ethoxy) -1,2,3,4-tetrahydro-2,7-naphthyridine;
2- (cyclobutylmethyl) -8- (1- (5-methylpyridin-2-yl) ethoxy) -1,2,3,4-tetrahydro-2,7-naphthyridine;
6- (Cyclobutylmethyl) -4- ((6-trifluoromethylpyridin-3-yl) methoxy) -5,6,7,8-tetrahydropyrido [4,3-d ] -pyrimidine.
14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
15. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, in the manufacture of a medicament for the treatment and/or prophylaxis of a sigma receptor associated disease or condition; preferably, the sigma receptor-related disease is a central nervous system disease; more preferably, the central nervous system disorder is depression, anxiety or bipolar disorder.
16. A process for the preparation of a compound of formula IA comprising the steps of:
scheme 1: reacting compound II or a salt thereof with R 1a -X 1 Obtaining an intermediate III 'by substitution reaction, and then reacting the intermediate III' with
Figure FDA0003607425290000051
Or a salt thereof, is converted into an intermediate IV 'through a ring closure reaction, the intermediate IV' is halogenated to obtain an intermediate V ', the intermediate V' is reacted with
Figure FDA0003607425290000052
Conversion to a compound of formula IA by a substitution reaction:
Figure FDA0003607425290000053
wherein W is N, X 1 、X 2 Independently selected from Cl, br or I, R 1a 、R 2a 、R 3a 、R 4a As defined in any one of claims 1 to 2;
scheme 2: reacting a compound IAa with
Figure FDA0003607425290000054
Reacting, converting into IAb, then performing reduction reaction to obtain IAc, and converting into compound IA by substitution reaction or ammoniation reduction reaction of IAc:
Figure FDA0003607425290000055
wherein W is CH, X 1 Is halogen, R 1a 、R 2a 、R 3a 、R 4a As defined in any one of claims 1 to 2.
17. A compound characterized by the structure:
Figure FDA0003607425290000061
wherein R is 9 Is halogen or hydroxy, R 2c Is H, halogen, C 1-5 Alkyl radical, C 1-5 Haloalkyl or C 1-5 An alkoxy group; preferably R 2c Is H, R 9 Is Cl, br or hydroxyl;
Figure FDA0003607425290000062
wherein R is 2d Is hydrogen, halogen, C 1-5 Alkyl radical, C 1-5 Haloalkyl or C 1-5 Alkoxy, preferably H, methyl or ethyl;
Figure FDA0003607425290000063
wherein R is 2e Is halogen, C 1-5 Alkyl radical, C 1-5 Haloalkyl or C 1-5 Alkoxy, preferably methyl or ethyl;
Figure FDA0003607425290000064
wherein R is 2f Is hydrogen, halogen, C 1-5 Alkyl radical, C 1-5 Haloalkyl or C 1-5 Alkoxy, preferably H, methyl or ethyl.
CN202210423392.7A 2021-04-29 2022-04-21 5,6,7,8-tetrahydropyrido [4,3-d ] pyrimidin-4-ol derivatives and uses thereof Pending CN115626922A (en)

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